Deleterious psychiatric outcomes following stress afflict many recently deployed combat Veterans. Recent evidence has shown that low doses of the anesthetic ketamine rapidly ameliorate depression, posttraumatic stress disorder (PTSD), anhedonia (a reduced capacity to experience pleasure), and suicidality within hours following a single administration. These effects extend to treatment-resistant populations, implicating ketamine as a novel and unique pharmacological option for treating psychiatric illnesses that disproportionately impact our combat Veterans. Despite these promising results, ketamine's use as a treatment outside of a hospital or clinic setting is limited due to its capacity to produce dissociative effects even at low doses and abuse liability. Ketamine's anesthetic effects are likely mediated by inhibition of the NMDA glutamate receptor (NMDAR) and as a consequence all of the drug's psychiatric effects (both negative and therapeutic), were assumed to have a similar underlying mechanism of action. Ketamine is rapidly metabolized into a number of metabolites, including hydroxynorketamines (HNKs) that are much less potent inhibitors of the NMDAR. We recently demonstrated (Nature, 2016) that the (2R,6R)-HNK metabolite exerts actions identical to ketamine in preclinical tests predictive of rapid and sustained antidepressant efficacy. Of significance, we found that even very high doses of (2R,6R)-HNK lack anesthetic and dissociative effects, as well as abuse liability in preclinical tests. Our goal is to develop an improved intervention for the treatment of stress-related disorders in Veterans, given what we know of ketamine's relevant pharmacological actions. Our preliminary data indicates that the (2R,6R)-HNK metabolite that is produced in humans after ketamine administration, may be an ideal treatment for PTSD and anhedonia afflicting Veterans exposed to stress. In Specific Aim #1, we will define the actions of ketamine compared to (2R,6R)-HNK in mouse tests of PTSD domains including conditioned fear responses and fear extinction, hyperarousal measured by acoustic startle responses, and electroencephalogram sleep abnormalities, both under control conditions and following stress. We will test effects of both pre- and post- symptom administration, predicting that (2R,6R)-HNK will be necessary and sufficient to exert the therapeutic effects of ketamine on different domains/endophenotypes associated with PTSD. In Specific Aim #2, we will determine actions of ketamine and its (2R,6R)-HNK metabolite on consummatory, anticipatory, and motivational subtypes of anhedonia, which has relevance to anhedonia observed as a symptom in patients with PTSD; as well as those with depression, schizophrenia, Parkinson's, and Alzheimer's disease. We anticipate that (2R,6R)-HNK will prove efficacious in several important experimental measures, and that successful completion of the project will provide the preclinical evidence that is needed for (2R,6R)-HNK to move forward in assessment as a clinical treatment for PTSD and anhedonia. This work could have an immediate impact, given that (2R,6R)-HNK is currently in drug development for depression. Thus, we believe that completion of the proposed experiments will provide a strong foundation from which a first-in-class treatment could be made available for our Veterans who are disproportionately affected by PTSD and anhedonia.